1 MRC Centre for Reproductive Health, University of Edinburgh2 Department of Clinical Physics and Bioengineering Royal Hospital for Children, Glasgow3 Centre for Clinical Brain Sciences, University of Edinburgh4 Princess Royal Maternity, Glasgow

Background: A key component of the management of opiate addiction during pregnancy is substitute opioid therapy, which has beneficial effects for the mother and fetus in the short term (1). Methadone is the recommended substitute in this context (2) and has been used for this purpose for more than four decades. However, there are uncertainties about the effect of exogenous opioids such as methadone on the developing brain. We aimed to summarise the neurodevelopmental, visual and neuroimaging outcomes of children prenatally exposed to methadone.

Methods: We searched MEDLINE, EMBASE and PsycINFO using search terms “methadone” and “prenatal” or “prenatal exposure” or “prenatal drug exposure” or “in utero” (PROSPERO registration number CRD42017063987). Studies including only mothers treated with alternative opiate substitutes during pregnancy were excluded. Outcomes were assessed in three domains: neurodevelopment; vision; neuroimaging. Where the studies reporting neurodevelopmental outcome used the same standardised assessment tool, quantitative data were pooled in statistical meta-analysis using R 3.2.2 (https://cran.r-project.org/). Effect sizes were expressed as weighted mean differences (WMD) and their 95% confidence intervals. Quality and bias were assessed using a modification of the GRADE scheme (3,4).

Results: We identified 1021 papers for screening: of these 112 full-text articles were assessed and 42 considered to be eligible for data synthesis. No randomised controlled trials included infant outcomes in any of the three domains. The quality of included studies was poor to intermediate, usually due to study design, poor methods reporting, low retention, confounding by prematurity or use of superseded assessment tools. Twenty-nine studies reported neurodevelopment; nine of these were case control studies using the Bayley Scales of Infant Development and were amenable to meta-analysis. At 18-24 months [7 studies: 170 exposed, 204 unexposed] Mental Development Index WMD was -4.3 (95% CI -7.24 to -1.63). Psychomotor Developmental Index WMD was -5.42 (95% CI -10.55 to -0.28) [4 studies: 94 exposed, 115 unexposed]. Eleven studies reported visual outcomes: atypical visual evoked potentials were reported in 4 out of 5 studies that measured this outcome, and increased prevalence of strabismus and nystagmus was a consistent finding in infancy and childhood. Two studies reported neonatal neuroimaging; one used cranial ultrasound and the other used MRI.

Conclusion: Current evidence does not confirm the safety of prenatal methadone exposure with respect to childhood outcomes. Neurodevelopment, behaviour, cognition and visual development appear to be altered in association with prenatal methadone exposure, but factors other than methadone per se may account for this finding. Future research into optimal management of pregnant women who use opioids should evaluate fetal/neonatal brain development and long term outcome.